In silico-designed mutations increase variable new-antigen receptor single-domain antibodies for VEGF(165) neutralization

The stability, binding, and tissue penetration of variable new-antigen receptor (VNAR) single-domain antibodies have been tested as part of an investigation into their ability to serve as novel therapeutics. V13 is a VNAR that recognizes vascular endothelial growth factor 165 (VEGF(165)). In the pre...

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Detalles Bibliográficos
Autores principales: Millán-Gómez, Dalia, Dueñas, Salvador, Muñoz, Patricia L. A., Camacho-Villegas, Tanya, Elosua, Carolina, Cabanillas-Bernal, Olivia, Escalante, Teresa, Perona, Almudena, Abia, David, Drescher, Florian, Fournier, Pierrick G. J., Ramos, Marco A., Mares, Rosa E., Paniagua-Solis, Jorge, Mata-Gonzalez, Teresa, Gonzalez-Canudas, Jorge, Hoffman, Robert M., Licea-Navarro, Alexei, Sánchez-Campos, Noemí
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2018
Materias:
Research Paper
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6021326/
https://www.ncbi.nlm.nih.gov/pubmed/29963259
http://dx.doi.org/10.18632/oncotarget.25549
Descripción
Sumario:The stability, binding, and tissue penetration of variable new-antigen receptor (VNAR) single-domain antibodies have been tested as part of an investigation into their ability to serve as novel therapeutics. V13 is a VNAR that recognizes vascular endothelial growth factor 165 (VEGF(165)). In the present study V13 was used as a parental molecule into which we introduced mutations designed in silico. Two of the designed VNAR mutants were expressed, and their ability to recognize VEGF(165) was assessed in vitro and in vivo. One mutation (Pro98Tyr) was designed to increase VEGF(165) recognition, while the other (Arg97Ala) was designed to inhibit VEGF(165) binding. Compared to parental V13, the Pro98Tyr mutant showed enhanced VEGF(165) recognition and neutralization, as indicated by inhibition of angiogenesis and tumor growth. This molecule thus appears to have therapeutic potential for neutralizing VEGF(165) in cancer treatment.

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